Vattathil Selina M, Blostein Freida, Miller-Fleming Tyne W, Davis Lea K, Wingo Thomas S, Wingo Aliza P
Department of Neurology, University of California, Davis, Sacramento, California, USA.
Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Alzheimers Dement. 2025 Jun;21(6):e70329. doi: 10.1002/alz.70329.
Neuropsychiatric symptoms in dementia (NPS) collectively refer to behavioral and psychological symptoms affecting individuals with mild cognitive impairment (MCI) or Alzheimer's disease or related dementia (ADRD). NPS are among the most troubling aspects of living with dementia but their treatments have limited efficacy. We aim to investigate genetic variants contributing to NPS to identify new therapeutic targets.
We performed a genome-wide association study (GWAS) for nine NPS domains measured by the Neuropsychiatric Symptom Inventory Questionnaire (NPI-Q) in 12,800 participants from Alzheimer's Disease Research Centers across the United States. We performed a replication analysis in two independent cohorts.
We found genome-wide significant signals for agitation, anxiety, apathy, delusions, and hallucinations that were driven by the apolipoprotein E (APOE) ε4 allele. We replicated these findings in ADNI and BioVU cohorts. Mediation analyses revealed that, except for apathy, MCI/ADRD severity only partially mediated the GWAS signals.
These findings suggest the APOE ε4 allele influences several NPS independently of and beyond its effect on ADRD.
Neuropsychiatric symptoms (NPS) are common in mild cognitive impairment and dementia. Effective NPS treatments are pressingly needed, and genetic studies can inform treatment targets to develop effective therapeutics. We conducted a genome-wide association study of NPS in over 12,800 individuals and a replication analysis in two independent cohorts. We found apolipoprotein E (APOE) single-nucleotide polymorphisms (SNPs) associated with multiple NPS domains beyond their effects on cognitive impairment.
痴呆症中的神经精神症状（NPS）共同指的是影响轻度认知障碍（MCI）、阿尔茨海默病或相关痴呆症（ADRD）患者的行为和心理症状。NPS是痴呆症患者生活中最困扰人的方面之一，但其治疗效果有限。我们旨在研究导致NPS的基因变异，以确定新的治疗靶点。
我们对来自美国各地阿尔茨海默病研究中心的12800名参与者，就通过神经精神症状问卷（NPI-Q）测量的九个NPS领域进行了全基因组关联研究（GWAS）。我们在两个独立队列中进行了重复分析。
我们发现载脂蛋白E（APOE）ε4等位基因驱动了与激越、焦虑、淡漠、妄想和幻觉相关的全基因组显著信号。我们在ADNI和BioVU队列中重复了这些发现。中介分析显示，除淡漠外，MCI/ADRD严重程度仅部分介导了GWAS信号。
这些发现表明APOE ε4等位基因独立于其对ADRD的影响并在其影响之外，还影响多种NPS。
神经精神症状（NPS）在轻度认知障碍和痴呆症中很常见。迫切需要有效的NPS治疗方法，基因研究可为开发有效治疗方法提供治疗靶点信息。我们对超过12800名个体进行了NPS的全基因组关联研究，并在两个独立队列中进行了重复分析。我们发现载脂蛋白E（APOE）单核苷酸多态性（SNP）与多个NPS领域相关，超出了它们对认知障碍的影响。
